PMID- 30923810
OWN - NLM
STAT- MEDLINE
DCOM- 20200731
LR  - 20200731
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 170
IP  - 1
DP  - 2019 Jul 1
TI  - Concurrent Inhibition of Vesicular Monoamine Transporter 2 Does Not Protect 
      Against 3,4-Methylenedioxymethamphetamine (Ecstasy) Induced Neurotoxicity.
PG  - 157-166
LID - 10.1093/toxsci/kfz085 [doi]
AB  - 3, 4-Methylenedioxymethamphetamine (MDMA) is a hallucinogenic amphetamine 
      derivative. The acute effects of MDMA are hyperthermia, hyperactivity, and 
      behavioral changes, followed by long-term serotonergic neurotoxicity in rats and 
      primates. However, the underlying mechanisms of MDMA neurotoxicity remain 
      elusive. We reported that pretreatment of rats with Ro 4-1284, a reversible 
      inhibitor of the vesicular monoamine transporter 2 (VMAT2), reduced MDMA-induced 
      hyperactivity in rats, abolished the hyperthermic response, and the long-term 
      neurotoxicity. Current studies focused on the effects of co- and/or 
      postinhibition of VMAT2 on the acute and chronic effects of MDMA and on the 
      dose-response relationship between MDMA-induced elevations in body temperature 
      and subsequent reductions in indolamine concentrations. Sprague Dawley rats were 
      treated with MDMA (20, 25, or 27.5 mg/kg sc), and either co- and/or posttreatment 
      with the VMAT2 inhibitor (10 mg/kg ip). Rats simultaneously treated with Ro 
      4-1284 and MDMA exhibited a more rapid increase in body temperature compared to 
      just MDMA. However, the duration of the elevated body temperature was 
      significantly shortened (approximately 3 h vs approximately 8 h, respectively). A 
      similar body temperature response was observed in rats posttreated (7 h after 
      MDMA) with Ro 4-1284. Despite decreases in the area under the curve (Deltatemp X 
      time) of body temperature caused by Ro 4-1284, there were no significant 
      differences in the degree of indolamine depletion between any of the MDMA-treated 
      groups. The results suggest that the neuroprotective effects of VMAT2 inhibition 
      is likely due to the indirect monoamine depleting effects of the Ro 4-1284 
      pretreatment, rather than by the direct inhibition of VMAT2 function.
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the 
      Society of Toxicology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Cholanians, Aram B
AU  - Cholanians AB
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, Arizona 85721.
FAU - Phan, Andy V
AU  - Phan AV
AD  - Department of Radiation Oncology, School of Medicine, University of Colorado 
      Denver, Denver, Colorado 80045.
FAU - Lau, Serrine S
AU  - Lau SS
AD  - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and 
      Health Sciences, Wayne State University, Detroit, Michigan 48201.
FAU - Monks, Terrence J
AU  - Monks TJ
AD  - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and 
      Health Sciences, Wayne State University, Detroit, Michigan 48201.
LA  - eng
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - R01 DA023525/DA/NIDA NIH HHS/United States
GR  - T32 ES007091/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Indoles)
RN  - 0 (Slc18a2 protein, rat)
RN  - 0 (Vesicular Monoamine Transport Proteins)
RN  - 303-75-3 (2H-Benzo(a)quinolizin-2-ol, 
      2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-)
RN  - 56480-48-9 (indolamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - 2H-Benzo(a)quinolizin-2-ol, 
      2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-/*pharmacology
MH  - Animals
MH  - Body Temperature/drug effects
MH  - Fever/chemically induced/drug therapy
MH  - Indoles/metabolism
MH  - Male
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neurotoxicity Syndromes/etiology/*prevention & control
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Vesicular Monoamine Transport Proteins/*antagonists & inhibitors
PMC - PMC6592187
OTO - NOTNLM
OT  - MDMA
OT  - Ro 4-1284
OT  - VMAT2
OT  - hyperthermia
OT  - neurotoxicity
EDAT- 2019/03/30 06:00
MHDA- 2020/08/01 06:00
PMCR- 2020/07/01
CRDT- 2019/03/30 06:00
PHST- 2019/03/30 06:00 [pubmed]
PHST- 2020/08/01 06:00 [medline]
PHST- 2019/03/30 06:00 [entrez]
PHST- 2020/07/01 00:00 [pmc-release]
AID - 5421825 [pii]
AID - kfz085 [pii]
AID - 10.1093/toxsci/kfz085 [doi]
PST - ppublish
SO  - Toxicol Sci. 2019 Jul 1;170(1):157-166. doi: 10.1093/toxsci/kfz085.